Cytochrome P-450 complex formation by dirithromycin and other macrolides in rat and human livers

Lindstrom, Terry D.; Hanssen, Ramon F.; Wrighton, Steven

doi:10.1128/aac.37.2.265

Cited by 58 publications

(23 citation statements)

References 13 publications

(16 reference statements)

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“…This result is consistent with the hypothesis that treatment with a single dose of ERY inhibits CYP3A in a competitive manner and exerts no effect on the enzyme activity measured in vitro. These data are consistent with previous studies demonstrating that ERY inhibits CYP3A through two mechanisms, namely a quasi-irreversible formation of metabolic intermediate complexes (Lindstrom et al, 1993) and by competitive inhibition. With respect to competitive inhibition by ERY, Yamano et al (2000) demonstrated an increase in MDZ AUC without MIC formation after a bolus injection of 10 mg/kg ERY to rats.…”

Section: Discussionsupporting

confidence: 83%

Inhibition of CYP3A by Erythromycin: In Vitro-In Vivo Correlation in Rats

et al. 2009

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ABSTRACT:The prediction of in vivo drug-drug interactions from in vitro enzyme inhibition parameters remains challenging, particularly when time-dependent inhibition occurs. This study was designed to examine the accuracy of in vitro-derived parameters for the prediction of inhibition of CYP3A by erythromycin (ERY). Chronically cannulated rats were used to estimate the reduction in in vivo and in vitro intrinsic clearance (CL int ) of midazolam (MDZ) after single and multiple doses of ERY; in vitro recovery of CL int was determined at 1, 2, 3, and 4 days after discontinuation of ERY. Enzyme inhibition parameters (k inact , K I , and K i ) of ERY were estimated in vitro by using untreated rat liver microsomes. In vivo enzyme kinetic analysis indicated that single and multiple doses of ERY (150 mg/kg i.v. infusion over 4 h) reduced MDZ CL int by reversible and irreversible mechanisms, respectively. CYP3A inactivation after multiple doses of ERY treatment reflected metabolic intermediate complex formation without a significant change in hepatic CYP3A2 mRNA. A physiologically based pharmacokinetic model of the interaction between ERY and MDZ predicted a 2.6-fold decrease in CYP3A activity after repeated ERY treatment using in vitro-estimated enzyme inhibition parameters and in vivo degradation half-life of the enzyme (20 ؎ 6 h). The observed -fold decreases were 2.3-fold and 2.1-fold for the in vitro-estimated CYP3A activity and the in vivo CL int , respectively. This study demonstrates that in vivo DDIs are predictable from in vitro data when the appropriate model and parameter estimates are available.The prediction of in vivo drug-drug interactions (DDIs) from in vitro data has met with limited success, and the general applicability of such predictions is unclear (von Moltke et al., 1998;Wang et al., 2004;Obach et al., 2005Obach et al., , 2007. As drugs capable of mechanismbased inhibition (MBI) have emerged as clinically important CYP3A inhibitors (Zhou et al., 2004), the uncertainty in predictive accuracy has increased. Approaches to predicting MBI-based DDIs vary from a relatively simple method using a single-inhibitor concentration to more complicated physiologically based pharmacokinetic (PBPK) models that consider the change of inhibitor and substrate concentrations with time (Mayhew et al., 2000;Ito et al., 2003;Wang et al., 2004;Obach et al., 2007). Changes in the amount of active enzyme in the presence of a mechanism-based inhibitor are estimated by using the in vitro enzyme inactivation parameters, K I and k inact , which can be used to predict the increase in the in vivo exposure of the substrate. These predictions often suffer from poor characterization of substrate and inhibitor properties in vitro and/or in vivo and from uncertainties in predictive model parameter values. For example, DDIs may reflect simultaneous reversible inhibition, irreversible inhibition, and induction at multiple sites of enzyme expression, but the relative contribution of each type of interaction in vivo may be difficult to d...

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Section: Discussionsupporting

confidence: 83%

Inhibition of CYP3A by Erythromycin: In Vitro-In Vivo Correlation in Rats

et al. 2009

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“…All those irreversible inhibitors showed significant decreases of IC so with incubation time, whereas IC so values of reversible inhibitors either remained stable or increased with incubation. This approach was successfully used to identify, not only potent irreversible CYP3A4 inhibitors such as macrolides (16), but also very weak ones such as The fluorescence-based CYP assay has been widely used for general inhibition evaluations (18,6), but using the assay for the identification of irreversible inhibitors has not been fully investigated (7). The current study has demonstrated the application of this method for distinguishing irreversible and reversible inhibition by using kinetic measurements.…”

Section: Validation Studiesmentioning

confidence: 99%

Rapidly distinguishing reversible and irreversible CYP450 inhibitors by using fluorometric kinetic analyses

Yan

Rafferty

Caldwell

et al. 2002

Eur. J. Drug Metab. Pharmacokinet.

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In this study we have evaluated the reliability of a fluorescence-based method used for rapid identification of irreversible CYP inhibitors (mechanism-based inhibitors). This was accomplished by comparing the time-dependence pattern of IC50 values from fluorometric kinetic measurements. For irreversible CYP inhibitors, IC50 values decreased as incubation proceeded. This was due to progressive inactivation of corresponding enzymes by reactive metabolites generated during the incubation. This change pattern was confirmed using a number of known irreversible CYP inhibitors, including furafylline, midazolam, erythromycin, clarithromycin, oleandomycin, 17alpha-ethynylestradiol and verapamil. The pattern was different in reversible inhibition, depending upon the compounds tested in the fluorometric kinetic assay. For some compounds, such as clotrimazole, IC50 values remained relatively stable, whereas other compounds, such as miconazole, terfenadine and ketoconazole showed a significant increase with incubation time. Monitoring tested compounds by LC-MS/MS during the incubation confirmed that increases of IC50 were probably caused by the loss of inhibitors, resulting from either metabolic degradation, or non-specific binding to microsomal proteins.

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“…This is due to oxidation of the inhibitor to form a nitrosoalkane species that forms a slowly reversible complex (MI-complex) with reduced heme in the CYP3A molecule (97, 98). Such compounds include macrolides like troleandomycin (99), oleandomycin (100), erythromycin (101), clarithromycin (102,103), roxithromycin (102), and dirithromycin (104); some antidepressants such as fluoxetine (105,106), nortriptyline (107), imipramine (106), and desipramine (106,107); and various miscellaneous drugs, including tiamulin (108), diltiazem (106), lidocaine (106), tamoxifen (106), and amiodarone (109).…”

Section: Formation Of Mi-complexesmentioning

confidence: 99%

In Vitro and in Vivo Drug Interactions Involving Human Cyp3a

Thummel

Wilkinson

1998

Annu. Rev. Pharmacol. Toxicol.

760

515

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Cytochrome P4503A (CYP3A) is importantly involved in the metabolism of many chemically diverse drugs administered to humans. Moreover, its localization in high amounts both in the small intestinal epithelium and liver makes it a major contributor to presystemic elimination following oral drug administration. Drug interactions involving enzyme inhibition or induction are common following the coadministration of two or more CYP3A substrates. Studies using in vitro preparations are useful in identifying such potential interactions and possibly permitting extrapolation of in vitro findings to the likely in vivo situation. Even if accurate quantitative predictions cannot be made, several classes of drugs can be expected to result in a drug interaction based on clinical experience. In many instances, the extent of such drug interactions is sufficiently pronounced to contraindicate the therapeutic use of the involved drugs.

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Cytochrome P-450 complex formation by dirithromycin and other macrolides in rat and human livers

Cited by 58 publications

References 13 publications

Inhibition of CYP3A by Erythromycin: In Vitro-In Vivo Correlation in Rats

Inhibition of CYP3A by Erythromycin: In Vitro-In Vivo Correlation in Rats

Rapidly distinguishing reversible and irreversible CYP450 inhibitors by using fluorometric kinetic analyses

In Vitro and in Vivo Drug Interactions Involving Human Cyp3a

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